KR100220605B1 - Novel antiviral 2,4-pyrimidinedione derivatives substituted with aikoxy carbonylmethylene or aryloxycarbonylmethylene on its n-1 position and process for the preparation thereof - Google Patents

Abstract

The present invention relates to a 2,4-pyrimidinedione derivative of the general formula (I) and a pharmaceutically acceptable salt thereof, a preparation method thereof, and an antiviral composition containing the same as an active ingredient. The compound is useful as a therapeutic agent for acquired immunodeficiency syndrome (AIDS) because of its high selectivity and physiological activity and low toxicity against viruses, particularly HIV-1.

(Wherein R ₁ , R ₂ , R _3, Y and Z are as defined in the specification).

Description

Novel antiviral 2,4-pyrimidinedione derivatives in which the N-1 position is substituted with an alkoxycarbonylmethylene group or an aryloxycarbonylmethylene group and a method for preparing the same ARYLOXYCARBONYLMETHYLENE ON ITS N-1 POSITION AND PROCESS FOR THE PREPARATION THEREOF}

The present invention relates to novel 2,4-pyrimidinedione derivatives and their pharmaceutically acceptable salts, methods for their preparation, intermediates useful for their preparation, which are useful as antiviral agents, in particular for the treatment of acquired immunodeficiency syndrome (AIDS). It relates to a preparation method and a pharmaceutical composition containing the same as an active ingredient.

Currently, chemotherapeutic agents used to treat AIDS include AZT (zidovudine: 3'-azido-3'-deoxythymidine), DDC (zalcitabine: 2 ', 3'-dideoxy Cytidine), DDI (didanosine: 2 ', 3'-deoxyinosine, D4T (stavudine: 3'-deoxy-2', 3'-didehydrothymidine), 3TC ( Lamivudine, nevirapine, indinavir, ritonavir and saquinavir, which are known to interfere with the replication of the virus. There is a side effect of the drug metabolites when used for a long time, as well as the resistance to the drug of the virus has been pointed out as a problem.

Therefore, much research is being conducted to develop a chemotherapeutic agent that minimizes these problems. According to recently published research papers, 2,4-pyrimidinedione-based compounds having an alkoxymethylene group at the N-1 position have excellent physiological activity and toxicity against human immunodeficiency virus (HIV). Are reported as few (see J. Med. Chem., 35, 4713, 1992; J. Med. Chem., 35, 337, 1992; J. Med. Chem., 34, 1508, 1991; J). Med. Chem., 34, 1394, 1991; J. Med. Chem., 34, 349, 1991; Molecular Pharm., 39, 805, 1991; Tet. Lett., 35, 4531, 1994; J. Med. Chem., 38, 2860, 1995; Nucleosides and Nucleotides, 14, 575, 1995; J. Med. Chem., 39, 2427, 1996; EP 0,449,726 A1; EP 0,420,763 A2; USP 5,318,972 and WO 95/18109 A1).

The present inventors have repeatedly studied to develop a compound having stronger physiological activity against HIV and less toxicity than previously developed 2,4-pyrimidinedione derivatives. The novel 2,4-pyrimidinedione derivatives substituted with a carbonylmethylene group or an aryloxycarbonylmethylene group have been found to exhibit strong physiological activity and low toxicity, thus completing the present invention.

It is an object of the present invention to provide 2,4-pyrimidinedione derivatives and pharmaceutically acceptable salts thereof which are excellent in selectivity and physiological activity against HIV and low in toxicity.

Another object of the present invention is to provide a method for preparing the compound.

Another object of the present invention is to provide a pharmaceutical composition comprising the compound.

It is a further object of the present invention to provide intermediate compounds useful in the preparation of these compounds and methods for their preparation.

In accordance with the above object, the present invention provides a 2,4-pyrimidinedione derivative of the general formula (I) and a pharmaceutically acceptable salt thereof.

Formula 1

(In the above formula,

R ₁ represents an alkynyl group or a benzyl hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ of the,

R ₂ and R ₃ are each independently a hydrogen atom, a halogen atom, a hydroxy group, C ₁ -C ₃ of a substituted or unsubstituted alkyl group, a fluorinated alkyl group, C ₁ -C ₈ alkoxy group, an alkenyl group of C ₂ -C ₈ , C ₂ -C ₈ alkynyl group or benzyl group,

Y is unsubstituted of C ₁ -C ₂₀ saturated or non-saturated primary, secondary, and tertiary alkoxy groups, C ₅ -C ₂₀ substituted or unsubstituted aryl alkoxy group, C ₅ -C ₂₀ or a substituted Heteroaryl alkoxy,

Z is substituted with at least one substituent selected from an oxygen atom, a sulfur atom, a carbonyl group, a methylene group or a halogen atom, an azido group, a cyano group, a hydroxy group, an amino group, an ester group of C ₁ -C ₄ , and an alkoxy group of C ₁ -C ₂₀ or Unsubstituted methylene group.)

According to another object of the present invention, there is provided a method for preparing a compound of formula (I) comprising the step of coupling the compound of formula (II) with a compound of formula (III).

(Wherein R ₁ , R ₂ , R ₃ , Y and Z are as defined above and X represents a halogen atom.)

In accordance with this another object, the present invention provides a compound of formula (II) which is an intermediate compound useful for the preparation of the compound of formula (I).

According to another object of the present invention, in the present invention, the compound of the general formula (IV) is methoxylated to obtain a chemical of the general formula (V), and the compound of the general formula (V) is substituted or substituted in the presence of a strong base. Coupling reaction with an unsubstituted arylacetonitrile to obtain a compound of formula (VI), and reacting the compound of formula (VI) with a base using a phase transfer catalyst in an air or oxygen atmosphere. It provides a compound of the following, and provides a method for producing a compound of the general formula (II-a) comprising the step of hydrolyzing the compound of the general formula (VII) with an acid.

(Wherein R ₁ , R ₂ , and R ₃ are as defined above).

According to this another object, in the present invention, a compound of formula (IV) is reacted with an alkali metal salt of benzyl alcohol to prepare a compound of formula (VII), and the following compound (VIII) is substituted in the presence of silver nitrate and a base. And reacting with an unsubstituted phenol to prepare a compound of formula (IX), wherein the compound of formula (IX) is hydrogenated in the presence of acetic acid and a palladium catalyst. Provided is a process for preparing the compound of b).

According to this another object, the present invention provides an antiviral composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Hereinafter, the present invention will be described in more detail.

Among the compounds of the general formula (I), compounds in which Z is an oxygen atom, a sulfur atom, a carbonyl group or a methylene group are particularly preferable.

Among the preferred compounds of the present invention, R ₁ is a substituted or unsubstituted C ₁ -C ₅ alkyl group, Y is a C ₁ -C ₁₀ primary, secondary and tertiary alkoxy group or C ₅ -C ₁₂ aryl The compound which is an alkoxy group is more preferable.

Among the more preferable compounds of the present invention, R ₁ is an ethyl group or an isopropyl group, R ₂ and R ₃ are each independently a hydrogen atom or a methyl group, Y is a methoxy group, an ethoxy group, a phenoxy group, a naphthoxy group, Most preferred are compounds in which Z is an oxygen atom or a carbonyl group.

The compound of formula (I) according to the present invention can be prepared by reacting a compound of formula (II) with a compound of formula (III) as shown in Scheme 1 below.

(Wherein R ₁ , R ₂ , R ₃ , Y and Z are as defined above and X represents a halogen atom.)

The reaction was carried out in the presence of a base such as anhydrous potassium carbonate or the like, in a polar solvent such as dimethylformamide under a nitrogen atmosphere at 0 ° C. to 100 ° C., the compound of Formula (II) and the compound of Formula (III): It may be carried out by reacting for 1 to 24 hours at a molar ratio of 0.8 to 1: 1.2.

The compounds of the general formula (II) used as starting materials for preparing the compounds of the general formula (I) of the present invention may be prepared according to the substituent Z, as shown in Scheme 2 below. It can manufacture by a method.

Method (i): when Z is C = O

Method (ii): when Z is O

(Wherein R ₁ , R ₂ and R ₃ are as defined above).

First, in method (i), compounds of formula (IV) which can be synthesized by known methods are prepared according to known methods (Ber., 52B, 869 (1919) and J. Med. Chem., 7, 808). (1964)), reacting with alkali metal salt of methanol such as sodium methoxide in methanol at room temperature to prepare a compound of formula (V) (step a). The compound of formula (V) is reacted with a substituted or unsubstituted arylacetonitrile at room temperature in a polar solvent such as dimethylformamide under a nitrogen atmosphere at room temperature in a polar solvent such as dimethylformamide. After preparation (step b), compound (VI) is reacted with a base such as 50% aqueous sodium hydroxide solution in a polar solvent such as dimethylformamide in an air or oxygen atmosphere in the presence of a phase transfer catalyst such as tetrabutylammonium bromide. After preparing the compound of formula (VII) (step c), the compound of formula (II-a) may be prepared by hydrolyzing compound (VII) with an acid such as hydrochloric acid (step d).

In method (ii), a compound of formula (IV) is reacted with an alkali metal salt of benzyl alcohol such as sodium benzyl oxide in benzyl alcohol to prepare a compound of formula (VIII) (step e), and compound (VIII) In a polar solvent such as dimethylformamide in the presence of a base such as sodium hydride and silver nitrate, a compound of formula (IX) is prepared by reacting with a substituted or unsubstituted phenol (step f), and compound (IX) is a solvent such as ethanol. In the presence of acetic acid and palladium catalyst in the hydrogenation at room temperature it can be prepared a compound of formula (II-b) (g step).

Another starting material, the compound of formula (III), can be synthesized using those commercially available for reagents or according to already known methods (Vogel's textbook of practical organic chemistry, 5th Ed.), As shown in Scheme 3 below. Can be used.

(Wherein X and Y are as defined above)

Compounds of formulas (XIII) and (XI) in Scheme 3 may use commercially available reagents.

The general formula (I) compounds of the present invention that may be prepared according to the methods as described above may include, but are not limited to, the following compounds.

Pharmaceutically acceptable salts of the compounds of general formula (I) of the present invention include alkali and alkaline earth metal salts thereof, such as sodium salts, potassium salts, magnesium salts and calcium salts.

Compounds of formula (I) of the present invention or pharmaceutically acceptable salts thereof are useful as antiviral agents, in particular anti-HIV agents.

Accordingly, the present invention also provides an antiviral composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the invention can be formulated in oral or injection dosage forms. Formulations for oral administration include, for example, tablets, capsules, etc. These formulations, in addition to the active ingredient, may contain diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants ( Examples: silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpicolidine, optionally starch, agar, alginic acid or its Disintegrants or boiling mixtures such as sodium salts and / or absorbents, colorants, flavors and sweeteners. Injectable formulations are preferably aqueous isotonic solutions or suspensions.

The composition may contain sterile and / or auxiliaries such as preservatives, stabilizers, hydrating or emulsifying accelerators, salts for regulating osmotic pressure and / or buffers and other therapeutically useful substances.

The formulations may be prepared by conventional mixing, granulating or coating methods and may contain the active ingredient in the range of about 0.1 to 75%, preferably about 1 to 50%. The unit dosage form for about 50-70 kg mammals contains about 10-200 mg of active ingredient.

Hereinafter, the present invention will be described in more detail based on the following Preparation Examples and Examples. However, these preparation examples and examples are only for illustrating the present invention, and the present invention should not be regarded as being limited only to these. In the examples, the temperature is in degrees Celsius (° C.) and all evaporation processes are carried out under reduced pressure, preferably about 15 to 100 mmHg, unless otherwise stated.

Preparation Example 1 Synthesis of 5-ethyl-6-benzoyl-2,4-pyrimidinedione

Step 1) Synthesis of 2,4-dimethoxy-5-ethyl-6- (α-cyanobenzyl) -1,3-pyrimidine

Ber., 52B, 869 (1919) and J. Med. Chem., 7, 808 (1964), 2,4-dimethoxy-5-ethyl-, prepared from 2,4,6-trichloro-5-ethyl-1,3-pyrimidine 30.4 g (0.15 M) of 6-chloro-1,3-pyrimidine and 17.8 g (0.15 M) of phenylacetonitrile are dissolved in 150 ml of dimethylformamide (DMF), and the reaction is cooled with an ice bath in a nitrogen atmosphere. 12 g (0.3 M) of 60% sodium hydride was added little by little and stirred for 30 minutes. The reaction was then stirred for another 16 hours at room temperature and neutralized by addition of glacial acetic acid. Diethyl ether was added, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then the residue was separated by column chromatography (eluent, ethyl acetate: hexane (1: 1)) to give 31 g (yield 73%). The title compound was obtained in the form of a white solid.

Melting point: 73-74 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.95 (3H, t, J = 7.5 Hz), 2.47-2.59 (2H, m), 3.97 (3H, s), 4.00 (3H, s), 5.31 (1H, s), 7.26-7.47 (5H, m).

Step 2) Synthesis of 2,4-dimethoxy-5-ethyl-6-benzoyl-1,3-pyrimidine

10 g (35 mmol) of the compound obtained in step 1 was dissolved in toluene (120 ml), and 2.28 g (7.5 mmol) of tetrabutylammonium bromide and 6 g of 50% sodium hydroxide aqueous solution were added thereto, and the mixture was stirred at room temperature for 12 hours. Then, diethyl ether was added to the reaction, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, diethyl ether: hexane (1: 3)) to give 9.1 g (94% yield) of the title compound as a white solid.

Melting point: 72-73 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.06 (3H, t, J = 7.5 Hz), 2.44 (2H, q, J = 7.5 Hz), 3.93 (3H, s), 4.05 (3H, s), 7.34 -7.89 (5H, m).

Step 3) Synthesis of 5-ethyl-6-benzoyl-2,4-pyrimidinedione

6 g (22 mmol) of the compound obtained in step 2 was added to 25 ml of concentrated hydrochloric acid, and the mixture was refluxed for 4 hours with stirring. The reaction was then cooled to room temperature and the resulting white precipitate was obtained by filtration, washed with distilled water and hexane and dried under reduced pressure to yield 4.8 g (yield 89%) of the title compound as a white solid.

Melting Point: 218-219 ° C

¹ H-NMR (200 MHz, CD ₃ OD) δ 0.98 (3H, t, J = 7.5 Hz), 2.17 (2H, q, J = 7.5 Hz), 7.58-8.03 (5H, m).

Preparation Example 2 5-ethyl-6- (3 ', 5'-dimethylbenzoyl) -2,4-pyrimidinedione

Step 1) 2,4-Dimethoxy-5-ethyl-6- (α-cyano-3 ', 5'-dimethylbenzyl) -1,3-pyrimidine

Ber., 52B, 869 (1919) and J. Med. Chem., 7, 808 (1964), 2,4-dimethoxy-5-ethyl-, prepared from 2,4,6-trichloro-5-ethyl-1,3-pyrimidine 30.4 g (0.15 M) of 6-chloro-1,3-pyrimidine and 21.8 g (0.15 M) of 3,5-dimethylphenylacetonitrile are dissolved in 150 ml of DMF, cooled in an ice bath under nitrogen atmosphere and 12 g of 60% sodium hydride ( 0.3 M) was added little by little with stirring and stirred for 1 hour. Subsequently, the reaction was stirred for an additional 16 hours at room temperature, neutralized by addition of glacial acetic acid, washed with diethyl ether, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluent, ethyl acetate: hexane (1:10)) to give 33.9 g (yield 70%) of the title compound as a white solid.

Melting point: 86-88 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.96 (3H, t, J = 7.4 Hz), 2.87 (6H, s), 2.46-2.58 (2H, m), 3.97 (3H, s), 4.01 (3H, s), 5.22 (1H, s), 6.94 (1H, s), 7.02 (2H, s).

Step 2) 2,4-Dimethoxy-5-ethyl-6- (3 ', 5'-dimethylbenzoyl) -1,3-pyrimidine

2.3 g (7.3 mmol) of the compound obtained in step 1 was dissolved in 40 ml of toluene, 0.7 g (2.7 mmol) of tetrabutylammonium bromide and 1.5 g of a 50% sodium hydroxide aqueous solution were added thereto, followed by stirring at room temperature under an air atmosphere for 15 hours. Subsequently, diethyl ether was added to the reaction, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was separated by column chromatography (eluent, diethyl ether: hexane (1: 3)) to obtain 2.0 g (yield 91%) of the title compound as a white solid.

Melting point: 97-99 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.04 (3H, t, J = 7.5 Hz), 2.33 (6H, s), 2.41 (2H, q, J = 7.5 Hz), 3.93 (3H, s), 4.04 (3H, s), 7.22 (1H, s), 7.45 (2H, s).

Step 3) 5-ethyl-6- (3 ', 5'-dimethylbenzoyl) -2,4-pyrimidinedione

3.4 g (11 mmol) of the compound obtained in Step 2 was added to 10 ml of concentrated hydrochloric acid, and the mixture was refluxed for 4 hours with stirring. The reaction was then concentrated under reduced pressure and the residue was recrystallized from methanol-chloroform to give 2.7 g (88% yield) of the title compound as a white solid.

Melting Point: 249 to 250 ° C

¹ H-NMR (200 MHz, CD ₃ OD) δ 0.97 (3H, t, J = 7.4 Hz), 2.17 (2H, q, J = 7.4 Hz), 2.39 (6H, s), 7.32 (1H, s), 7.50 (2H, s).

Preparation Example 3 5-Isopropyl-6-benzoyl-2,4-pyrimidinedione

Step 1) 2,4-Dimethoxy-5-isopropyl-6- (α-cyanobenzyl) -1,3-pyrimidine

Ber., 52B, 869 (1919) and J. Med. Chem., 7, 808 (1964), 2,4-dimethoxy-5-iso, prepared from 2,4,6-trichloro-5-isopropyl-1,3-pyrimidine 32.5 g (0.15 M) of propyl-6-chloro-1,3-pyrimidine and 17.6 g (0.15 M) of phenylacetonitrile are dissolved in 150 ml of DMF, and the reaction is cooled in an ice bath under nitrogen atmosphere and stirred with 60% sodium hydride. 12 g (0.3 M) was added little by little. The reaction was then stirred at ambient temperature for 16 hours, then neutralized by addition of glacial acetic acid, washed with diethyl ether, dried over anhydrous magnesium sulfate and filtered. The residue obtained by concentration under reduced pressure was separated by column chromatography (eluent, diethyl ether: hexane (1:10)) to give 29.5 g (yield 66%) of the title compound as a white solid.

Melting point: 80-82 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.02 (3H, d, J = 6.9 Hz), 1.05 (3H, d, J = 6.9 Hz), 3.02 (1H, m), 3.95 (3H, s), 3.99 (3H, s), 5.31 (1H, s), 7.20-7.30 (5H, m).

Step 2) 2,4-Dimethoxy-5-isopropyl-6-benzoyl-1,3-pyrimidine

4.5 g (15 mmol) of the compound obtained in step 1 was dissolved in 30 ml of toluene, and 1.6 g (5 mmol) of tetrabutylammonium bromide and 3 g of 50% sodium hydroxide aqueous solution were added thereto, and the mixture was stirred at room temperature for 12 hours. Subsequently, diethyl ether was added to the reaction, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was separated by column chromatography (eluent, diethyl ether: hexane (1: 3)) to give 4.27 g (98% yield) of the title compound as a white solid.

Melting point: 105-106 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.16 (6H, d, J = 7.0 Hz), 2.83 (1H, m), 3.92 (3H, s), 4.05 (3H, s), 7.40-7.90 (5H, m).

Step 3) 5-isopropyl-6-benzoyl-2,4-pyrimidinedione

6 g (21 mmol) of the compound obtained in Step 2 was added to 25 ml of concentrated hydrochloric acid, and the mixture was refluxed for 4 hours with stirring. Subsequently, the reaction was cooled to room temperature and the resultant precipitate was obtained by filtration, washed with distilled water and hexane and dried under reduced pressure to give 4.7 g (yield 87%) of the title compound as a white solid.

Melting point: 220-221 ° C

¹ H-NMR (200 MHz, CD ₃ OD) δ 1.16 (6H, d, J = 7.0 Hz), 2.45 (1H, m), 7.61-8.02 (5H, m).

Preparation Example 5 5-isopropyl-6- (3 ', 5'-dimethylbenzoyl) -2,4-pyrimidinedione

Step 1) 2,4-Dimethoxy-5-isopropyl-6- (α-cyano-3 ', 5'-dimethylbenzyl) -1,3-pyrimidine

Ber., 52B, 869 (1919) and J. Med. Chem., 7, 808 (1964), 2,4-dimethoxy-5-iso, prepared from 2,4,6-trichloro-5-isopropyl-1,3-pyrimidine 26.8 g (0.18 M) of propyl-6-chloro-1,3-pyrimidine and 26.8 g (0.18 M) of 3,5-dimethylphenylacetonitrile were dissolved in 200 ml of DMF, and the reaction was cooled with an ice bath under nitrogen atmosphere. 14.8 g (0.37 M) of% sodium hydride was added little by little and stirred for about 1 hour. Subsequently, the reaction was stirred at room temperature for 16 hours, neutralized by addition of glacial acetic acid, diethyl ether, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was separated by column chromatography (eluent, ethyl acetate: hexane (1: 9)) to give 42 g (yield 70%) of the title compound as a white solid.

Melting point: 107-108 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.11 (3H, d, J = 7.0 Hz), 1.13 (3H, d, J = 7.0 Hz), 2.29 (6H, s), 3.07 (1H, m), 4.00 (3H, s), 4.04 (3H, s), 5.37 (1H, s), 6.94 (1H, s), 7.00 (2H, s).

Step 2) 2,4-Dimethoxy-5-isopropyl-6- (α-cyano-3 ', 5'-dimethylbenzoyl) -1,3-pyrimidine

15 g (46 mmol) of the compound obtained in step 1 was dissolved in 150 ml of toluene, and 2.37 g (7.4 mmol) of tetrabutylammonium bromide and 10 g of a 50% sodium hydride aqueous solution were added thereto, followed by stirring at room temperature for 17 hours in the presence of air. Subsequently, diethyl ether was added to the reaction mixture, which was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then the residue was separated by column chromatography (eluent, diethyl ether: hexane (1: 3)) to obtain 13.8 g. (Yield 95%) of the title compound was obtained in the form of a white solid.

Melting point: 149-150 ° C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.20 (6H, d, J = 6.9 Hz), 2.37 (6H, s), 2.81 (1H, m), 3.96 (3H, s), 4.08 (3H, s) , 7.28 (1 H, s), 7.47 (2 H, s).

Step 3) 5-Isopropyl-6- (3 ', 5'-dimethylbenzoyl) -2,4-pyrimidinedione

9.6 g (30 mmol) of the compound obtained in Step 2 was added to 50 ml of concentrated hydrochloric acid, and the mixture was refluxed for 4 hours with stirring. Subsequently, the reaction was cooled to room temperature, and the resultant precipitate was obtained by filtration, washed with distilled water and hexane, and dried under reduced pressure to obtain 8 g (yield 92%) of the title compound as a white solid.

Melting Point: 238-239 ° C

¹ H-NMR (200 MHz, CD ₃ OD / CDCl ₃ ) δ 1.16 (6H, d, J = 6.9 Hz), 2.35-2.49 (7H, m), 7.35 (1H, s), 7.53 (2H, s).

Preparation Example 5 5-Ethyl-6-phenoxy-2,4-pyrimidinedione

Step 1) 2,4-Dibenzyloxy-5-ethyl-6-chloro-1,3-pyrimidine

2.17 g (94.6 mmol) of sodium metal was added to 80 ml of benzyl alcohol under nitrogen atmosphere, and the mixture was stirred at room temperature for about 2 hours. The reaction was then cooled in a water bath and described in Ber., 52B, 869 (1919) and J. Med. Chem., 7, 808 (1964)] was added 10.5 g (49.6 mmol) of 2,4,6-trichloro-5-ethyl-1,3-pyrimidine prepared according to a method known in the art, and stirred for 30 minutes. The reaction was further stirred at room temperature for 24 hours. Next, benzyl alcohol was removed by distillation under reduced pressure, and the residue was dissolved in diethyl ether, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then the obtained residue was purified by column chromatography (eluate, diethyl ether: hexane ( 4:96)) to give 14 g (yield 80%) of the title compound as a white solid.

Melting point: 53-54 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.14 (3H, t, J = 7.4 Hz), 2.70 (2H, q, J = 7.4 Hz), 5.41 (2H, s), 5.45 (2H, s), 7.34 -7.53 (10 H, m).

Step 2) 2,4-Dibenzyloxy-5-ethyl-6-phenoxy-1,3-pyrimidine

2.65 g (28.2 mmol) of phenol was dissolved in 30 ml of DMF, cooled in an ice bath under nitrogen atmosphere, and then 1.13 g (28.2 mmol) of 60% sodium hydride was added little by little with stirring. Subsequently, the reaction temperature was raised to room temperature, 2.6 g (16.9 mmol) of nitric acid and 5.0 g (14.1 mmol) of the compound obtained in Step 1 were added thereto, followed by stirring for 24 hours in an oil bath at 100-110 ° C. The reaction was then cooled to room temperature, the reaction was filtered through a celite layer, the celite layer was washed with diethyl ether, and the filtrates were combined and washed. The residue obtained by drying over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure was separated by column chromatography (eluent, diethyl ether: hexane (1:10)) to give 4.55 g (yield 78%) of the title compound as a white solid. Got it.

Melting point: 48-49 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.15 (3H, t, J = 7.5 Hz), 2.64 (2H, q, J = 7.5 Hz), 5.12 (2H, s), 5.42 (2H, s), 7.06 -7.43 (15 H, m).

Step 3) 5-ethyl-6-phenoxy-2,4-pyrimidinedione

4.3 g (10.4 mmol) of the compound obtained in step 2 was dissolved in 80 ml of anhydrous ethanol, 500 mg of 10% Pd-C and 10 drops of glacial acetic acid were added, followed by stirring at room temperature under a hydrogen atmosphere for about 20 hours. The reaction was then filtered through a celite bed and the residue obtained by concentration of the filtrate under reduced pressure was separated by column chromatography (eluent, methanol: dichloromethane (4:96)) to give 2.0 g (83% yield) of the title. The compound was obtained in the form of a white solid.

Melting Point: 242-243 ° C

¹ H-NMR (200 MHz, CD ₃ OD) δ 0.95 (3H, t, J = 7.5 Hz), 2.25 (2H, q, J = 7.5 Hz), 7.05-7.45 (5H, m).

Preparation Example 6 5-Ethyl-6- (3 ', 5'-dimethylphenoxy) -2,4-pyrimidinedione

Step 1) 2,4-Dibenzyloxy-5-ethyl-6- (3 ', 5'-dimethylphenoxy) -1,3-pyrimidine

2.07 g (16.9 mmol) of 3,5-dimethylphenol was dissolved in 18 ml of DMF, cooled in an ice bath under nitrogen atmosphere, and 0.68 g (16.9 mmol) of 60% sodium hydride was added little by little with stirring. Subsequently, 1.56 g (10.15 mmol) of silver nitrate and 3 g (8.46 mmol) of the compound obtained in Step 1 of Preparation Example 5 were added thereto, followed by stirring for 24 hours in an oil bath at 100-110 ° C. Subsequently, the reaction was cooled to room temperature, filtered through a celite layer, the celite layer was washed with diethyl ether, and the filtrates were combined and washed with water. After drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure, the obtained residue was separated by column chromatography (eluent, chloroform: hexane (2: 1)) to give 3.14 g (yield 84%) of the title compound as a white solid. Got it.

Melting point: 61-62 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.14 (3H, t, J = 7.5 Hz), 2.33 (6H, s), 2.62 (2H, q, J = 7.5 Hz), 5.14 (2H, s), 5.41 (2H, s), 6.72 (2H, s), 6.85 (1H, s), 7.23-7.41 (13H, m).

Step 2) 5-ethyl-6- (3 ', 5'-dimethylphenoxy) -2,4-pyrimidinedione

2.8 g (6.36 mmol) of the compound obtained in step 1 was dissolved in 60 ml of anhydrous ethanol, 300 mg of 10% Pd-C and 10 drops of glacial acetic acid were added, followed by stirring at room temperature for 20 hours under a hydrogen atmosphere. The reaction was then filtered through a celite bed, and the residue obtained by concentration of the filtrate under reduced pressure was separated by column chromatography (eluent, methanol: dichloromethane (4:96)) to give 1.4 g (85% yield) of the title. The compound was obtained in the form of a white solid.

Melting Point: 221-222 ° C

¹ H-NMR (200 MHz, CD ₃ OD) δ 0.90 (3H, t, J = 7.4 Hz), 2.17-2.25 (8H, m), 6.62 (2H, s), 6.78 (1H, s).

Preparation Example 7 5-isopropyl-6-phenoxy-2,4-pyrimidinedione

Step 1) 2,4-Dibenzyloxy-5-isopropyl-6-chloro-1,3-pyrimidine

2.04 g (88.7 mmol) of sodium metal was added to 80 ml of benzyl alcohol in a nitrogen atmosphere, followed by stirring at room temperature for 2 hours. The reaction was then cooled in a water bath and described in Ber., 52B, 869 (1919) and J. Med. Chem., 7, 808 (1964)] added 10.5 g (46.6 mmol) of 2,4,6-trichloro-5-isopropyl-1,3-pyrimidine prepared according to the method known in the above, and at room temperature for 24 hours. Stirred. Next, benzyl alcohol was distilled off under reduced pressure, the residue was dissolved in diethyl ether, washed with water, dried over anhydrous magnesium sulfate, filtered and the residue obtained by concentration under reduced pressure was purified by column chromatography (eluate, diethyl ether: hexane (3). : 97)) to give 14 g (yield 82%) of the title compound as a white solid.

Melting point: 77-78 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.26 (6H, d, J = 7.0 Hz), 3.45 (1H, m), 5.37 (2H, s), 5.42 (2H, s), 7.30-7.49 (10H, m).

Step 2) 2,4-Dibenzyloxy-5-isopropyl-6-phenoxy-1,3-pyrimidine

2.54 g (27 mmol) of phenol was dissolved in 30 ml of DMF, cooled in an ice bath under nitrogen atmosphere, and then 1.08 g (27 mmol) of 60% sodium hydride was added little by little with stirring. Next, 2.49 g (16.2 mmol) of silver nitrate and 5.0 g (13.5 mmol) of the compound obtained in Step 1 were added thereto, and the reaction was stirred for 24 hours in an oil bath at 100-110 ° C. The reaction mixture was then cooled to room temperature, filtered through a celite bed, the celite bed was washed with diethyl ether, the filtrate was collected and washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Separation by column chromatography (eluent, diethyl ether: hexane (1:10)) gave 5.2 g (yield 90%) of the title compound as a white solid.

Melting point: 61-62 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.30 (6H, d, J = 7.1 Hz), 3.44 (1H, m), 5.10 (2H, s), 5.41 (2H, s), 7.04-7.41 (15H, m).

Step 3) 5-isopropyl-6-phenoxy-2,4-pyrimidinedione

5 g (11.7 mmol) of the compound obtained in step 2 was dissolved in 80 ml of anhydrous ethanol, 10 mg of Pd-C and 10 drops of glacial acetic acid were added, followed by stirring at room temperature for 20 hours under a hydrogen atmosphere. The reaction was then filtered through a celite bed and concentrated under reduced pressure. The residue was separated by column chromatography (eluent, methanol: dichloromethane (4:96)) to give 2.6 g (yield 81%) of the title compound as white. Obtained in solid form.

Melting Point: 214-215 ° C

¹ H-NMR (200 MHz, CD ₃ OD) δ 1.16 (6H, d, J = 7.0 Hz), 2.98 (1H, m), 7.04-7.45 (5H, m).

Preparation Example 8 5-isopropyl-6- (3 ', 5'-dimethylphenoxy) -2,4-pyrimidinedione

Step 1) 2,4-Dibenzyloxy-5-isopropyl-6- (3 ', 5'-dimethylphenoxy) -1,3-pyrimidine

3.3 g (27 mmol) of 3,5-dimethylphenol was dissolved in 30 ml of DMF, cooled in an ice bath under nitrogen atmosphere, and 1.08 g (27 mmol) of 60% sodium hydride was added little by little with stirring. Then, 2.49 g (16.2 mmol) of silver nitrate and 4.98 g (13.5 mmol) of the compound obtained in Step 1 of Preparation Example 7 were added thereto, and the reaction was stirred for 24 hours in an oil bath at 100-110 ° C. Subsequently, the temperature of the reaction was lowered to room temperature, the reaction was filtered through a celite layer, the celite layer was washed with diethyl ether, the filtrates were combined and washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was separated by column chromatography (eluent, chloroform: hexane (2: 1)) to give 5.1 g (yield 83%) of the title compound as a white solid.

Melting point: 70-71 ° C

¹ H-NMR (200 MHz, CD ₃ OD) δ 1.29 (6H, d, J = 7.0 Hz), 2.32 (6H, s), 3.41 (1H, m), 5.12 (2H, s), 5.40 (2H, s ), 6.70 (2H, s), 6.84 (1H, s), 7.18-7.44 (13H, m).

Step 2) 5-Isopropyl-6- (3 ', 5'-dimethylphenoxy) -2,4-pyrimidinedione

4.5 g (9.91 mmol) of the compound obtained in step 1 was dissolved in 80 ml of anhydrous ethanol, 10 mg of Pd-C and 10 drops of glacial acetic acid were added, followed by stirring at room temperature for 20 hours under a hydrogen atmosphere. The reaction was then filtered through a celite bed and concentrated under reduced pressure. The residue was separated by column chromatography (eluent, methanol: dichloromethane (4:96)) to give 2.5 g (yield 92%) of the title compound as white. Obtained in solid form.

Melting Point: 229-230 ° C

¹ H-NMR (200 MHz, CD ₃ OD) δ 1.20 (6H, d, J = 7.1 Hz), 2.33 (6H, s), 3.35 (1H, m), 6.64 (2H, s), 6.83 (1H, s ).

Example 1 Synthesis of 1-methoxycarbonylmethylene-5-ethyl-6-benzoyl-2,4-pyrimidinedione (Compound No. 1)

244 mg (1 mmol) of the compound obtained in Preparation Example 1 and 138 mg (1 mmol) of anhydrous potassium carbonate were dissolved in 5 ml of dimethylformamide (DMF), and 113 µl (1.2 mmol) of methyl bromoacetate was added thereto, followed by stirring at room temperature for about 16 hours. It was. Subsequently, diethyl ether was added, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the residue was separated by column chromatography (eluent; ethyl acetate: hexane (1: 2)) to give 162 mg (yield 51%). ) Was obtained in the form of a white solid.

Melting point: 134-135 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.96 (3H, t, J = 7.4 Hz), 2.08-2.22 (2H, m), 3.59 (3H, s), 4.27-4.32 (2H, m), 7.52- 8.00 (5H, m), 9.01 (1H, s).

Example 2: Synthesis of 1-ethoxycarbonylmethylene-5-ethyl-6- (3 ', 5'-dimethylbenzoyl) -2,4-pyrimidinedione (Compound No. 2)

130 mg (yield 38%) of the title compound was reacted in the same manner as in Example 1, except that the compound of Preparation Example 2 was used instead of the compound of Preparation Example 1, and ethyl bromoacetate was used instead of methyl bromoacetate. Obtained in the form of a white solid.

Melting point: 125-126 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.06 (3H, t, J = 7.4 Hz), 1.22 (3H, t, J = 7.2 Hz), 2.15-2.35 (2H, m), 2.49 (6H, s) 4.15 (2H, q, J = 7.2 Hz), 4.37 (2H, s), 7.44 (1H, s), 7.67 (2H, s), 8.75 (1H, s).

Example 3: Synthesis of 1-phenoxycarbonylmethylene-5-isopropyl-6-benzoyl-2,4-pyrimidinedione (Compound No. 3)

62 mg of the starting material was reacted in the same manner as in Example 1, except that the compound of Preparation Example 3 was used instead of the compound of Preparation Example 1, and phenylbromoacetate was used instead of methyl bromoacetate. (Yield 31%) of the title compound was obtained in the form of a white solid.

Melting Point: 141-143 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.18 (3H, d, J = 6.9 Hz), 1.23 (3H, d, J = 6.9 Hz), 2.39 (1H, m), 4.49 (1H, d, J = 10.0 Hz), 4.60 (1H, d, J = 10.0 Hz), 6.80-8.07 (10H, m), 9.10 (1H, s).

Example 4: Synthesis of 1- (2-naphthoxycarbonylmethylene) -5-isopropyl-6- (3 ', 5'-dimethylbenzoyl) -2,4-pyrimidinedione (Compound No. 4)

In the same manner as in Example 1, except that the amount of the starting material was halved, and the compound of Preparation Example 4 was used instead of the compound of Preparation Example 1, and 2-naphthylbromoacetate was used instead of methylbromoacetate. Reaction gave 89 mg (yield 38%) of the title compound as a white solid.

Melting Point: 163 to 165 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.16 (3H, d, J = 3.6 Hz), 1.22 (3H, d, J = 3.6 Hz), 2.29-2.45 (7H, m), 4.44-4.70 (2H, m), 6.93-7.84 (10H, m), 8.84 (1H, s).

Example 5: Synthesis of 1-methoxycarbonylmethylene-5-ethyl-6-phenoxy-2,4-pyrimidinedione (Compound No. 5)

The amount of starting material was halved, and 67 mg (yield 44%) of the title compound was reacted in the same manner as in Example 1 except that the compound of Preparation Example 5 was used instead of the compound of Preparation Example 1. Got it.

Melting point: 149-150 ° C.

¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.95 (3H, t, J = 7.5 Hz), 2.23 (2H, q, J = 7.5 Hz), 3.72 (3H, s), 4.56 (2H, s), 7.00 -7.45 (5H, m), 8.59 (1H, s).

Example 6: Synthesis of 1-ethoxycarbonylmethylene-5-ethyl-6- (3 ', 5'-dimethylphenoxy) -2,4-pyrimidinedione (Compound No. 6)

190 mg (yield 55%) of the title compound were reacted in the same manner as in Example 1, except that the compound of Preparation Example 5 was used instead of the compound of Preparation Example 1, and ethyl bromoacetate was used instead of methyl bromoacetate. Obtained in the form of a white solid.

Melting point: 189 ~ 190 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.18 (6H, d, J = 7.0 Hz), 1.25 (3H, t, J = 7.0 Hz), 2.33 (6H, s), 2.82 (1H, m), 4.18 (2H, q, J = 7.0 Hz), 4.46 (2H, s), 6.58 (2H, s), 6.81 (1H, s), 8.60 (1H, s).

Example 7: Synthesis of 1-phenoxycarbonylmethylene-5-isopropyl-6- (phenoxy) -2,4-pyrimidinedione (Compound No. 7)

190 mg (yield 50%) of the title compound was reacted in the same manner as in Example 1, except that the compound of Preparation Example 7 was used instead of the compound of Preparation Example 1, and phenylbromoacetate was used instead of methylbromoacetate. Obtained in the form of a white solid.

Melting point: 193-194 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.16 (6H, d, J = 7.0 Hz), 2.82 (1H, m), 4.73 (2H, s), 6.93-7.45 (10H, m), 8.81 (1H, s).

Example 8: Synthesis of 1- (2-naphthoxycarbonylmethylene) -5-isopropyl-6- (3 ', 5'-dimethylphenoxy) -2,4-pyrimidinedione (Compound No. 8)

In the same manner as in Example 1 except that the amount of the starting material was halved, and the compound of Preparation Example 8 was used instead of the compound of Preparation Example 1, and 2-naphthoxybromoacetate was used instead of methylbromoacetate. Reaction gave 80 mg (yield 35%) of the title compound as a white solid.

Melting Point: 185 to 186 ° C

¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.17 (6H, d, J = 7.0 Hz), 2.30 (6H, s), 2.83 (1H, s), 4.75 (2H, s), 6.64 (2H, s) , 6.83 (1 H, s), 7.04-7.87 (7 H, m), 9.00 (1 H, s).

Examples 9-32 (Synthesis of Compound Nos. 9-32)

Various compounds were prepared in a similar manner to the above examples and are shown in Table 1 below.

Compound number R ₁ R ₂ R ₃ Y Z ¹ H-NMR (200 MHz, CDCl ₃ ) δ Melting Point (℃) 9 Isopropyl CH ₃ CH ₃ CH ₃ O 1.14 (6H, d, J = 7.0 Hz), 2.29 (6H, s), 2.78 (1H, m), 3.68 (3H, s), 4.44 (2H, s), 6.55 (2H, s), 6.76 (1H , s). 132-133 10 Isopropyl CH ₃ CH ₃ ethyl O 1.18 (6H, d, J = 7.0 Hz), 1.25 (3H, t, J = 7.0 Hz), 2.33 (6H, s), 2.82 (1H, m), 4.18 (2H, q, J = 7.0 Hz), 4.46 (2H, s), 6.58 (2H, s), 6.81 (1H, s), 8.60 (1H, s). 158-159 11 Isopropyl CH ₃ CH ₃ Phenyl O 1.15 (6H, d, J = 7.0 Hz), 2.29 (6H, s), 2.81 (1H, s), 4.69 (2H, s), 6.60 (2H, s), 6.80 (1H, s), 6.93-7.38 (5H, m), 8.82 (1H, s) 175-176 12 ethyl CH ₃ CH ₃ CH ₃ O 0.93 (3H, t, J = 7.4 Hz), 2.25 (2H, q, J = 7.4 Hz), 2.29 (6H, s), 3.69 (3H, s), 4.49 (2H, s), 6.56 (2H, s ), 6.77 (1 H, s). 157 13 ethyl CH ₃ CH ₃ Phenyl O 0.95 (3H, t, J = 7.0 Hz), 2.23 (2H, q, J = 7.0 Hz), 2.29 (6H, s), 4.74 (2H, s), 6.62 (2H, s), 6.81 (1H, s ), 6.94-7.38 (5H, m), 9.05 (1H, s). 135-136 14 ethyl CH ₃ CH ₃ 2-naphthyl O 0.97 (3H, t, J = 7.4 Hz), 2.19-2.31 (8H, m), 4.81 (2H, s), 6.67 (2H, s), 6.85 (1H, s), 7.05-7.85 (7H, m) , 8.85 (1 H, s). 203-205 15 Isopropyl CH ₃ CH ₃ CH ₃ C = O 1.14 (3H, d, J = 7.0 Hz), 1.16 (3H, d, J = 7.0 Hz), 2.29-2.39 (7H, m), 3.58 (3H, s), 4.24 (1H, s), 4.28 (1H , s), 7.33 (1H, s), 7.57 (2H, s), 9.10 (1H, s). 150-151 16 Isopropyl CH ₃ CH ₃ ethyl C = O 1.09-1.29 (9H, m), 2.31-2.40 (7H, m), 4.05 (2, q, J = 7.2 Hz), 4.22 (1H, d, J = 9.2 Hz), 4.35 (1H, d, J = 9.2 Hz), 7.35 (1H, s), 7.60 (2H, s), 10.05 (1H, s) syrup 17 Isopropyl CH ₃ CH ₃ Phenyl C = O 1.16 (3H, d, J = 7.2 Hz), 1.22 (3H, d, J = 7.2 Hz), 2.34-2.40 (7H, m), 4.49 (1H, s), 4.52 (1H, s), 6.83-7.36 (6H, m), 7.62 (2H, s), 8.80 (1H, s). 104-105 18 ethyl CH ₃ CH ₃ CH ₃ C = O 1.06 (3H, t, J = 7.3 Hz), 2.25-2.35 (2H, m), 2.49 (6H, s), 3.71 (3H, s), 4.39 (2H, s), 7.44 (1H, s), 7.66 (2H, s), 9.42 (1H, s) 132 19 ethyl CH ₃ CH ₃ Phenyl C = O 1.08 (3H, t, J = 7.4 Hz), 2.15-2.38 (2H, m), 2.46 (6H, s), 4.63 (2H, s), 6.95-6.99 (2H, m), 7.27-7.42 (3H, m), 7.45 (1 H, s), 7.71 (2 H, s), 8.84 (1 H, s). 153-154 20 ethyl CH ₃ CH ₃ 2-naphthyl C = O 1.09 (3H, t, J = 7.4 Hz), 2.20-2.40 (2H, m), 2.47 (6H, s), 4.70 (2H, s), 7.06-7.93 (10H, m), 9.23 (1H, s) . 101-102

Compound number R ₁ R ₂ R ₃ Y Z ¹ H-NMR (200 MHz, CDCl ₃ ) δ Melting Point (℃) 21 Isopropyl H H CH ₃ O 1.15 (6H, d, J = 7.0 Hz), 2.78 (1H, m), 3.68 (3H, s), 4.47 (2H, s), 6.96-7.42 (5H, m), 8.08 (1H, s). 141-143 22 Isopropyl H H ethyl O 1.15-1.30 (9H, m), 2.83 (1H, m), 4.17 (2H, q, J = 7.1 Hz), 4.48 (2H, s), 6.98-7.45 (6H, m), 8.61 (1H, s) . 125-126 23 Isopropyl H H 2-naphthyl O 1.17 (6H, d, J = 7.0 Hz), 2.83 (1H, m), 4.78 (2H, s), 7.03-7.86 ((12H, m), 8.53 (1H, s). 202-203 24 ethyl H H ethyl O 0.95 (3H, t, J = 7.5 Hz), 1.23 (3H, t, J = 7.1 Hz), 2.27 (2H, q, J = 7.5 Hz), 4.21 (2H, q, J = 7.1 Hz), 4.62 ( 2H, s), 7.01-7.44 (5H, m), 8.79 (1H, s). 154-155 25 ethyl H H Phenyl O 0.97 (3H, t, J = 7.4 Hz), 2.26 (2H, q, J = 7.4 Hz), 4.81 (2H, s), 6.96-7.47 (10H, m) 8.71 (1H, s). 171-172 26 ethyl H H 2-naphthyl O 0.99 (3H, t, J = 7.5 Hz), 2.27 (2H, q, J = 7.5 Hz), 4.88 (2H, s), 7.07-7.88 (12H, m) 8.79 (1H, s). 204-206 27 Isopropyl H H CH ₃ C = O 1.16 (3H, d, J = 6.6 Hz), 1.23 (3H, d, J = 6.6 Hz), 2.32 (1H, m), 3.57 (3H, s), 4.20 (1H, d, J = 10.2 Hz), 4.30 (1H, doublet, J = 10.2 Hz), 7.53-8.02 (5H, m), 8.75 (1H, s). 178-179 28 Isopropyl H H ethyl C = O 1.07-1.64 (9H, m), 2.35 (1H, m), 3.98-4.45 (4H, m), 7.54-8.05 (5H, m), 8.81 (1H, s). 163-164 29 Isopropyl H H 2-naphthyl C = O 1.22 (3H, d, J = 6.1 Hz), 1.29 (3H, d, J = 6.1 Hz), 2.42 (1H, m), 4.50 (1H, d, J = 10.0 Hz), 4.75 (1H, d, J = 10.0 Hz), 6.98-8.14 (12H, m), 8.75 (1H, s). 205-206 30 ethyl H H ethyl C = O 1.00 (3H, t, J = 7.3 Hz), 1.15 (3H, t, J = 7.1 Hz), 2.10-2.26 (2H, m), 4.07 (2H, q, J = 7.1 Hz), 4.28-4.40 (2H m), 7.55-8.06 (5H, m), 8.97 (1H, s). 146-147 31 ethyl H H Phenyl C = O 1.00 (3H, t, J = 7.4 Hz), 2.12-2.27 (2H, m), 4.54-4.58 (2H, m), 6.84-8.08 (10H, m), 9.09 (1H, s). 174 32 ethyl H H 2-naphthyl C = O 1.01 (3H, t, J = 7.2 Hz), 2.16-2.25 (2H, m), 4.62-4.70 (2H, m), 6.97-8.11 (12H, m), 9.19 (1H, s). 201-202

Effect test and toxicity test

In order to determine the effect of the compound of the present invention was carried out in vitro HIV-1 inhibitory effect test in accordance with a known method (J. Med. Chem., 34, 349 (1991)) as follows. MT-4 cells were used as host cells to investigate the extent to which the compounds of the present invention inhibit the cytotoxicity of virus-infected MT-4 cells.

First, MT-4 cells were dispersed in the culture medium at a concentration of 1 × 10 ⁴ cells / well, and then inoculated with HIV-1 to 500 TCID ₅₀ (a concentration at which 50% of cells are infected) / well. Immediately after inoculation, 100 μl of the cell dispersion was transferred to a flat microtiter plate containing a sample of the compound of the present invention, and cultured at 37 ° C. for about 4 days to 5 days, and then the virus inhibition effect was determined using the MTT method. In addition, cytotoxicity was also determined by experimentally measuring the viability of the virus-infected cells by the MTT method. AZT was used as a reference compound.

The results of testing the compounds of the present invention by the test method are summarized in Table 2 below.

Example number CD ₅₀ (μg / ml) ^* ED ₅₀ (μg / ml) ^** SI (CD ₅₀ / ED ₅₀ ) ^*** One 110.32 0.016 6,895 2 12.64 0.0028 4,514 3 114.14 0.00143 79,818 4 8.22 <0.001 > 8,220 5 120.13 1.56 77 6 33.15 0.138 240 7 140.42 0.345 407 8 12.44 0.00695 1,790 9 88.50 0.000566 156,360 10 15.12 0.0088 1,718 11 9.61 0.0156 616 12 80.26 0.0069 11,631 13 13.25 0.019 697 14 11.99 0.10 119 15 21.86 0.0069 3,168 16 2.26 <0.001 > 2,260 17 9.81 0.0077 1,274 18 24.88 0.001027 24,255 19 12.50 0.0022 5,681 20 8.98 0.0044 2,040 21 93.26 0.115 811 22 85.39 1.34 63 23 12.27 0.58 21 24 78.64 0.16 491 25 120.13 1.56 77 26 92.14 10.92 8 27 125.66 0.0024 52,358 28 110.96 0.046 2,412 29 16.39 0.015 1,092 30 110.32 0.016 6,895 31 85.69 0.37 231 32 112.41 4.086 27 AZT 0.588 0.001161 506

CD ₅₀ : 50% cell damage concentration on MT-4 cells

** ED ₅₀ : 50% inhibition of HIV-1 infection

*** SI: selectivity index = CD ₅₀ / ED ₅₀

From the above results, it can be seen that the compound of the present invention is low in cytotoxicity and excellent in HIV-1 inhibitory effect, thus having high selectivity and physiological activity against HIV-1.

As described above, the novel 2,4-pyrimidinedione derivatives of the present invention, wherein the N-1 position is substituted with an alkoxycarbonylmethylene group or an aryloxycarbonylmethylene group, has high selectivity and bioactivity for HIV-1. Because of its high toxicity and low toxicity, it is useful as a treatment for AIDS.

Claims (8)

A compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula 1

In the above formula, R ₁ represents a hydrogen atom, a halogen atom or an alkyl group of C ₁ -C ₆ , R ₂ and R ₃ each independently represent a hydrogen atom, a halogen atom or an alkyl group of C ₁ -C ₃ , Y represents a C ₁ -C ₆ primary, secondary and tertiary alkoxy group or a C ₆ -C ₁₀ arylalkoxy group, Z represents an oxygen atom, a sulfur atom, a carbonyl group or a methylene group. The method of claim 1, R ₁ is an ethyl group or isopropyl group, R ₂ and R ₃ are each independently a hydrogen atom or a methyl group, Y is a methoxy group, an ethoxy group, a phenoxy group, or a naphthoxy group, and Z is an oxygen atom or a carbonyl group Or a pharmaceutically acceptable salt thereof. The method of claim 1, The following compounds or pharmaceutically acceptable salts thereof: 1-methoxycarbonylmethylene-5-isopropyl-6- (3 ', 5'-dimethylphenoxy) -2,4-pyrimidinedione (Compound No. 9); 1-ethoxycarbonylmethylene-5-isopropyl-6- (3 ', 5'-dimethylphenoxy) -2,4-pyrimidinedione (Compound No. 10); 1-phenoxycarbonylmethylene-5-isopropyl-6- (3 ', 5'-dimethylphenoxy) -2,4-pyrimidinedione (Compound No. 11); 1- (2-naphthoxy) carbonylmethylene-5-isopropyl-6- (3 ', 5'-dimethylphenoxy) -2,4-pyrimidinedione (Compound No. 8); 1-methoxycarbonylmethylene-5-ethyl-6- (3 ', 5'-dimethylphenoxy) -2,4-pyrimidinedione (Compound No. 12); 1-ethoxycarbonylmethylene-5-ethyl-6- (3 ', 5'-dimethylphenoxy) -2,4-pyrimidinedione (Compound No. 6); 1-phenoxycarbonylmethylene-5-ethyl-6- (3 ', 5'-dimethylphenoxy) -2,4-pyrimidinedione (Compound No. 13); 1- (2-naphthoxy) carbonylmethylene-5-ethyl-6- (3 ', 5'-dimethylphenoxy) -2,4-pyrimidinedione (Compound No. 14); 1-methoxycarbonylmethylene-5-isopropyl-6- (3 ', 5'-dimethylbenzoyl) -2,4-pyrimidinedione (Compound No. 15); 1-ethoxycarbonylmethylene-5-isopropyl-6- (3 ', 5'-dimethylbenzoyl) -2,4-pyrimidinedione (Compound No. 16); 1-phenoxycarbonylmethylene-5-isopropyl-6- (3 ', 5'-dimethylbenzoyl) -2,4-pyrimidinedione (Compound No. 17); 1- (2-naphthoxy) carbonylmethylene-5-isopropyl-6- (3 ', 5'-dimethylbenzoyl) -2,4-pyrimidinedione (Compound No. 4); 1-methoxycarbonylmethylene-5-ethyl-6- (3 ', 5'-dimethylbenzoyl) -2,4-pyrimidinedione (Compound No. 18); 1-ethoxycarbonylmethylene-5-ethyl-6- (3 ', 5'-dimethylbenzoyl) -2,4-pyrimidinedione (Compound No. 2); 1-phenoxycarbonylmethylene-5-ethyl-6- (3 ', 5'-dimethylbenzoyl) -2,4-pyrimidinedione (Compound No. 19); 1- (2-naphthoxy) carbonylmethylene-5-ethyl-6- (3 ', 5'-dimethylbenzoyl) -2,4-pyrimidinedione (Compound No. 20); 1-methoxycarbonylmethylene-5-isopropyl-6-phenoxy-2,4-pyrimidinedione (Compound No. 21); 1-ethoxycarbonylmethylene-5-isopropyl-6-phenoxy-2,4-pyrimidinedione (Compound No. 22); 1-phenoxycarbonylmethylene-5-isopropyl-6-phenoxy-2,4-pyrimidinedione (Compound No. 7); 1- (2-naphthoxy) carbonylmethylene-5-isopropyl-6-phenoxy-2,4-pyrimidinedione (Compound No. 23); 1-methoxycarbonylmethylene-5-ethyl-6-phenoxy-2,4-pyrimidinedione (Compound No. 5); 1-ethoxycarbonylmethylene-5-ethyl-6-phenoxy-2,4-pyrimidinedione (Compound No. 24); 1-phenoxycarbonylmethylene-5-ethyl-6-phenoxy-2,4-pyrimidinedione (Compound No. 25); 1- (2-naphthoxy) carbonylmethylene-5-ethyl-6-phenoxy-2,4-pyrimidinedione (Compound No. 26); 1-methoxycarbonylmethylene-5-isopropyl-6-benzoyl-2,4-pyrimidinedione (Compound No. 27); 1-ethoxycarbonylmethylene-5-isopropyl-6-benzoyl-2,4-pyrimidinedione (Compound No. 28); 1-phenoxycarbonylmethylene-5-isopropyl-6-benzoyl-2,4-pyrimidinedione (Compound No. 3); 1- (2-naphthoxy) carbonylmethylene-5-isopropyl-6-benzoyl-2,4-pyrimidinedione (Compound No. 29); 1-methoxycarbonylmethylene-5-ethyl-6-benzoyl-2,4-pyrimidinedione (Compound No. 1); 1-ethoxycarbonylmethylene-5-ethyl-6-benzoyl-2,4-pyrimidinedione (Compound No. 30); 1-phenoxycarbonylmethylene-5-ethyl-6-benzoyl-2,4-pyrimidinedione (Compound No. 31); And 1- (2-naphthoxy) carbonylmethylene-5-ethyl-6-benzoyl-2,4-pyrimidinedione (Compound No. 32). A process for preparing a compound of formula (I) according to claim 1 comprising coupling a compound of formula (II) to a compound of formula (III): Formula 2

Formula 3

Wherein R ₁ , R ₂ , R ₃ , Y and Z are as defined in claim 1 and X represents a halogen atom. The method of claim 4, wherein The compound of formula (II) and the compound of formula (III) are reacted for 1 to 24 hours at a molar ratio of 1: 0.8 to 1: 1.2 in a nitrogen atmosphere at 0 to 100 ° C. in a polar solvent in the presence of a base. How to. The compound of formula (IV) is methoxylated to obtain a compound of formula (V), and the compound of formula (V) is subjected to a coupling reaction with a substituted or unsubstituted arylacetonitrile in the presence of a strong base. The compound of formula (VI) is obtained, and the compound of formula (VI) is reacted with a base using a phase transfer catalyst under an air or oxygen atmosphere to obtain a compound of formula (VII). Method for preparing a compound of formula (II-a) including the step of hydrolyzing with: Formula 4

Formula 5

Formula 6

Formula 7

Formula 8

Wherein R ₁ , R ₂ , and R ₃ are as defined in claim 1. The compound of formula (IV) is reacted with an alkali metal salt of benzyl alcohol to prepare a compound of formula (VIII), and compound (VIII) is reacted with a substituted or unsubstituted phenol in the presence of silver nitrate and a base. A process for preparing a compound of formula (II-b) comprising preparing a compound of formula (IX) and hydrogenating the compound of formula (IX) in the presence of acetic acid and a palladium catalyst: Formula 4

Formula 9

Formula 10

Formula 11

Wherein R ₁ , R ₂ , and R ₃ are as defined in claim 1. An antiviral composition comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.